SUMMARY ABSTRACT The inability of these present therapies to mitigate the devastating effects of sepsis indicates that more knowledge of the patho-physiology of septic condition is needed not only if we are to develop better, more effective interventions but to identify for whom/ when these interventions will be most efficacious. Our laboratory along with several others has had sustained interest in not only how sepsis, as produced by cecal ligation and puncture (CLP), differentially effects the immune response observed in divergent tissue sites, but to what extent these aberrations in myeloid and/or lymphoid cell functions can contribute to changes in septic morbidity/ mortality. Importantly, we have observed that CLP induces marked changes in 3 key regulatory T- cell populations, i.e., -T-, CD4+CD25+ native T-regulatory -, and NKT-cells, within the spleen, liver and intestine, which we have found to either have the capacity to induced marked immune suppression or have an affect on the animal's capacity to ward off septic mortality. Unlike, the classic -CD4 T-cells these various `innate regulatory T-cell' populations share a unique capacity to respond rapidly to inflam-matory, infectious and/or wound associate stimuli, i.e., innate activation. Thus, they have the capacity to serve as sentinels of tissue homeostasis, potentially regulating the response to infection and/or injury. Here we propose to test the central hypothesis that it is the differential activation of resident tissue NKT-cells (via inhibitory [i.e., PD- 1:PD-L1/L2] and/or stimulatory receptor[s] and/or inflammatory mediator[s]), that directly drives not only the classic immune cell (i.e., -CD4 T-cell, macrophage [M] and/or dendritic cell [DC]), but also local organ dysfunctions. To test this, the following Aims are proposed. Aim 1: We will determine the capacity of NKT-cell deficiency to alter the organ function, bacterial clearance, wound healing and/or classic immune cell responsiveness during sepsis. Aim 2: We will determine not only if resident tissue NKT-cells and/or -CD4 T-cells exhibit changes of various inhibitory (PD-1, PD-L1/L2) or receptors and/or are sources of pro (IL-2, IFN-)-/ anti (IL-10, TGF-)-inflammatory cytokines, but also what roles these agents play in the development of changes in these `innate regulatory T-cells' in sepsis. Aim 3: We will delineate the extent to which the expression of signaling molecules, i.e., STAT1/ 4/ 6, p38 MAPK, SOCS1/ 3, or SHP-2 alter the frequency/ functions of either resident tissue NKT-cells and/or their expression of PD-1, PD-L1 or PD-L2. Aim 4: We will, alternatively, examine the degree to which resident tissue M, DC and/or their expression of PD-1, PD-L1 or PD-L2 regulate sepsis-induced changes seen in NKT-cells. It is our belief that the results of these studies will provide information that not only will allow us to better understand the pathobiology of sepsis induced immune dysfunction, but also its attenuation.